Endothelin and gelatinases in renal changes following blockade of nitric oxide synthase in hypertensive rats.
We investigated the involvement of matrix metalloproteinases (MMPs), tissue inhibitor (TIMP) and endothelin-1 (ET-1) in the renal damage in spontaneously hypertensive rats (SHR) following nitric oxide (NO) deprivation. SHR received Nomega-nitro-L-arginine methyl ester (L-NAME) from 5 wk-old for a period of 30 days. An ETA antagonist, FR139317 was used. We gave SHR FR139317 alone and cotreatment with L-NAME. L-NAME caused systemic hypertension, decrease in plasma nitrate/nitrite, increases in blood urea nitrogen and creatinine, impairment of glomerular dynamics. NO deprivation reduced the renal tissue cGMP, but it increased the collagen volume fraction, number of sclerotic glomeruli, arteriolar injury score and glomerular injury score. In addition, L-NAME elevated the plasma ET-1 at day 5. Cotreatment with FR139317 alleviated the L-NAME-induced functional and structural changes of renal glomeruli. L-NAME administration for 5 to 10 days resulted in decreases in MMP2 and MMP9 with increasing TIMP2. After L-NAME for 15 days, opposite changes (increases in MMP2 and MMP9 with a decrease in TIMP2) were observed. FR139317 cotreatment ameliorated the L-NAME-induced changes in MMP2 and MMP9 throughout the 30-day observation period. The ETA antagonist cotreatment attenuated the L-NAME-induced increase in TIMP2 before day 15, but not after day 20. The results indicate that ET-1, MMPs and TIMP are involved at the early stage (before 10 days) of glomerular sclerosis and arteriosclerosis with functional impairment following NO deprivation. The changes in MMPs and TIMP at the late stage (after 20 days) may be a compensatory response to prevent further renal damage.
Yang
Yi-Ling
YL
Institute of Biotechnology, National Chia-Yi University, Chiayi Republic of China.
Liu
Demeral David
DD
Hsieh
Nan-Kuang
NK
Chen
Hsing I
HI
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001806:Blood Urea Nitrogen; D003094:Collagen / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018093:Gelatinases / Q000378:metabolism*; D005919:Glomerular Filtration Rate / Q000502:physiology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D001381:Azepines; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007211:Indoles; D009566:Nitrates; D019716:Tissue Inhibitor of Metalloproteinase-2; C079574:FR 139317; D003094:Collagen; D003404:Creatinine; D019001:Nitric Oxide Synthase; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester